CA1320131C - Aqueous pharmaceutical preparation containing 11.beta.-hydroxy steroids - Google Patents
Aqueous pharmaceutical preparation containing 11.beta.-hydroxy steroidsInfo
- Publication number
- CA1320131C CA1320131C CA000588137A CA588137A CA1320131C CA 1320131 C CA1320131 C CA 1320131C CA 000588137 A CA000588137 A CA 000588137A CA 588137 A CA588137 A CA 588137A CA 1320131 C CA1320131 C CA 1320131C
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- Prior art keywords
- cyclodextrin
- steroid
- beta
- water
- solubility
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nanotechnology (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Pain & Pain Management (AREA)
- Biophysics (AREA)
- Rheumatology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
Abstract
ABSTRACT
Aqueous pharmaceutical preparation The present invention relates to a new pharmaceutical preparation for local application comprising an aqueous solution of 11.beta.-hydroxy-16.alpha.,17.alpha.,21-trimethyl-.DELTA.1,4-pregnadiene-3,20-dione and a .beta.-cyclodextrine derivative.
Aqueous pharmaceutical preparation The present invention relates to a new pharmaceutical preparation for local application comprising an aqueous solution of 11.beta.-hydroxy-16.alpha.,17.alpha.,21-trimethyl-.DELTA.1,4-pregnadiene-3,20-dione and a .beta.-cyclodextrine derivative.
Description
~3~91~
Aqueous ~harmaceutical preParation The present invention relates to a new pharmaceuti-cal preparation for local application comprising an aqueous solution of ll~-hydroxy~ ,17a,21-trimethyl-1~4-pregnadiene-3,2O-dione (hereinafter called Org 6216 or the Steroid) and a ~-cyclodextrine derivative.
More particularly the said new composition is par-ticularly useful for ophthalmolo~ical purposes, viz. for the treatment of infections in or at the eyes~
In general, ll~-hydroxy steroidæ (corticosteroids) including the Steroid are known for their potent local anti-inflammatory activity, see for example US patent : 3,947,478. Moreover, the Steroid did not expose any significant systemic effect when administered locally.
However, it is also generally known that most cor-ticosteroids when applied to the eyes are held responsi-ble for an unacceptable increase of the intra ocular pressure (I.O.P.) which render ~hem absolutely unsuit-~: able for any ~phthalmological application. Fortunately, ~ however, it was recently found that contrary t~ other : corti~osteroids the Steroid ~id not increase I.O.P., so that also an ophthalmological application of the Steroid could he considered.
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132~31 The Steroid, however, has one significant drawback which hitherto blocked virtually any practical applica-tion namely its extremely poor solubility in aqueous systems.
For local application in the form of injection preparations, eye-drops, ear-drops, nose-sprays or the like the desired concentration of the Steroid in water could not be sbtained. For topical application in the form of a gel, foams, cream or ointment (on water basis) large amounts of the Steroid were necessary in order to have very small amounts penetrated ~hrough the skin.
In general it is known that ~,~ and r-cyclodextrins may form in~lusion complexes with various organic or inorganic compounds and as a result may increase the solubility of these compounds. See e.g. the review article of Saenger in Angewandte Chemie Int. Ed. 19, 344 (198~).
It is Applicant's own experience an~ supported by literature data that the solubility of a compound in water may increase very roughly by a factor 2-500 provided said compound is able to ~orm an inclusion-complex with one of the cyclodextrins.
The Steroid, however, would not benefit from such increase because its original solubility in water of ap-proximately 5x10-4 mg/ml would most ideally increase at most up to a level of about 0,1 mg/ml which is still in-sufficient for local administration o~ the Steroid in general and more in particular for ophthalmological ap-plication. Practical solubility tests carried out with ~,~ and r-cyclodextrin only confirmed this expectation.
Surprisingly, however, it was found that an inclusion complex formed between the Steroid and 2,6-dimethyl-~-cyclodextrin increased the solubility of the Stèroid in water from the original level of 5xlO 4 mg/ml up to a level o~ about 10 mg~ml, which means an increase of the solubility with the unexpectedly high factor of 10.000.
Thi6 increase of the Steroid's solubility in water renders a practical application of the Steroid possible in pharmaceutical preparations for local administration and especially in ophthalmological preparations.
The present invention therefore encompasses a phar-maceu~ical preparation for local administration, and especially an ophthalmological preparation comprising an aqueous solution of ll~-hydroxy-16~,17~,21-trimethyl-4_ pregnadiene 3,20-dione (the Steroid, Org 6216) and a partially alkylated ~-cyclodextrin.
A partially alkylated ~-cyclodextrin is a deriva-tive of ~-cyclodextrin (or cyclohepta~amylose) in which one or more hydroxy groups are alkylated. Examples of such partially alkylated ~-cyclodextrins are the 2-hydroxypropyl, 6-methyl, 2,3-dimethyl and in particu-lar the 2,6-dimethyl-~-cyclodextrin.
The solubility o~ the Steroid in water increases with increasing concentrations of partially alkylated ~-cyclodextrin until this solubility reaches its level-off phase or maximal level. This maximal level is ob-tained using relatively large amounts of partially alky-lated ~-cyalodextrins, roughly O.2-0.3 mmol. partially alkylated ~-cyclodextrin per mililiter water.
The maximal solubility o the 5tersid in water using 2,6-dimethyl~-cyclodextrin as the solubilizing agent amounts to about 9-10 mg/ml; at this level the 2,6-dimethyl-~-cyclodextrin concentration required is about 0,28 millimol per ml. A further increase of the cyclodextrin concentration contributes less effectively to a further improve~ent of the Steroid's sslubility.
The graph shows the increase o~ the solubility of the Steroid (Org 621~) with increasing 2,6-dimethyl-~-cyclodextrin concentrations.
' ~3~131 The solubility studies were per~ormed according to the method described ~elow which is well known in the litrature. Excess amounts of the Steroid were added to a~ueous solutions of 2,~-dimethyl-~cyclodextrin. These suspensions were shaken at room temperature during 5 days followad by an equilibration period of 3 days at room temperature. Then an aliquot was centrifuged and the supernatant was fil~ere~ t~hrough a 0,45 ~m membrane filter (Millipore: HV4, Millex). The samples were anal-ysed with the Perkin ~lmer Lambda 5 W/VIS spectropho-tometer. The absorbance was read and compared with a blanc and standard calibration curve. ~rom these data the concentration o~ Steroid dissolved in water was cal-culated. After calculation of the amount of Steroid dis-solved, a phase-solubility diagram was constructed by plotting the dissolved amounts of Steroid as a function of the concentratiGn of 2,6-dimethyl-~-cyclodextrin (see Graph).
From the curve obtained the complex stabllity con-stant K was calculated using the formula:
slope K =
SO (l-sloPe) SO = saturation concentration of Steroid without 2,6-dimethyl-~-cyclodxtrin.
slope = the slope of the initial part of the curve.
This complex-stability constant K i5 also a measure for the solubility of the Steroid in water. The higher this complex-stability constant, the better is the sta-bility of the complex and the higher is the solubility in water.
For comparati~e purposes the unexpected increase of solubility of the Steroid in water using 2,6 dimethyl-~-cyclodextrin, is compared with other more common cy-clodextrins. Th~ results are described in the following table:
.
~rad~ - ~ar~
1~0~
Cyclodextrin Steroid reference compounds Org 6216 _ - . 1 ~-cyclodextr~n K (ml.mmol. ) 380 Solubility (mg/ml) 4 x 10-2 R-cylodextriln X (ml.mmol.~ ) 3400 Solubility (mg/ml) 5 x 10 2 r-cvclodextr~ l K (ml.mmol. ) 9600 I
Solubility (mg/ml) 7 x 10 2 Part. alkylated cyclodextrin 2r6~dimethyl~
~aYsal~ I I
K (ml.mmol l) l 58000 Solubility (mg/ml) l 9 Solubility without cyclodextrin, mg/ml l 7 x 10-4 . ~ . - . , I
Besides the essential ingredients Steroid, par-tially methylated ~-cyclodextrin and water, the pharma-ceutical preparation according to the invention may con-tain other active substances and/or pharmaceutical aux-iliaries.
The preparation may optionally contain for example, preservatives, viscosity increasing agents, agents for rendering the solution isotonic, buf~ers for adapting the desired pH, surfac~ants etc., as well as the usual pharmaceutically acceptable carriers and/or diluents.
As already said the preparation according to the invention may be used for all kinds of local administra-tion, e.g. as injection preparation, intranasal prepara-tion, ear-drops, topical preparation (gel, ointment, foam, cream~, but is preferably used for ophthalmologi-cal purposes.
.
6 132~l3l A preparation for local administration is a prepa-ration that i~ locally active and does not exert a sig-nificant systemic effect.
The concentration of the Steroid in the pharmaceu-tical preparation according ~o the invention may vary somewhat depending upon the way of administration. The usual concentration, however, varies between 1 and 10 mg and more par~icularly between 5 and 10 mg per mililiter water. For ophthalmological purposes where usually only one or two drops are applied the concentration of the Steroid i~ preferably as high as possible, viz. about 9-10 mg per ml water.
~xamples 1. ToE~çal qel 2,6-dimethyl-~-cyclodextrin 50,0 g Org 6216 0,9 g pectine 5.0 g sugar 30,0 g water to 100 ml prepare complex, add pectin and ~issolve, add sugar adju~t pH to 3-4.
2. o/w emulslon (w = water phase, o = oil phase) 2,6-dimethyl-~-cylodextrin 185 g w org 6216 3,3 g w sodium laurylsulphate10 g w stearyl alcohol 250 g w white petrolatum250 g w methylhydroxybenzoate0,7 g w propylhydroxybenzoa~e3,7 g w water 370 g w propylene glycol120 g w 1192,7 g prepare oil ph~se and water phase separately at ele-vated temperature~ then, add oil pha~e to water phase and homogenize.
:;
' . ~ :
~, .
7 132n~ 31 3. Opthalmic solution (eye drop) Org 6216 4,5 g 2,6 dimethyl-~-cyclodextrin 250,0 g polyvinylalcohol 7,0 g Na2HPO4 3,8 g NaH2PO4 0, 8 g Chlorobutanol 2,5 g NaCl to isotonic Water for injections to 500 ml prepare complex, add other components, adjust to volume.
Aqueous ~harmaceutical preParation The present invention relates to a new pharmaceuti-cal preparation for local application comprising an aqueous solution of ll~-hydroxy~ ,17a,21-trimethyl-1~4-pregnadiene-3,2O-dione (hereinafter called Org 6216 or the Steroid) and a ~-cyclodextrine derivative.
More particularly the said new composition is par-ticularly useful for ophthalmolo~ical purposes, viz. for the treatment of infections in or at the eyes~
In general, ll~-hydroxy steroidæ (corticosteroids) including the Steroid are known for their potent local anti-inflammatory activity, see for example US patent : 3,947,478. Moreover, the Steroid did not expose any significant systemic effect when administered locally.
However, it is also generally known that most cor-ticosteroids when applied to the eyes are held responsi-ble for an unacceptable increase of the intra ocular pressure (I.O.P.) which render ~hem absolutely unsuit-~: able for any ~phthalmological application. Fortunately, ~ however, it was recently found that contrary t~ other : corti~osteroids the Steroid ~id not increase I.O.P., so that also an ophthalmological application of the Steroid could he considered.
:: :
: ~ ' .
.
, . " ~ , ' .
.
~' ~
132~31 The Steroid, however, has one significant drawback which hitherto blocked virtually any practical applica-tion namely its extremely poor solubility in aqueous systems.
For local application in the form of injection preparations, eye-drops, ear-drops, nose-sprays or the like the desired concentration of the Steroid in water could not be sbtained. For topical application in the form of a gel, foams, cream or ointment (on water basis) large amounts of the Steroid were necessary in order to have very small amounts penetrated ~hrough the skin.
In general it is known that ~,~ and r-cyclodextrins may form in~lusion complexes with various organic or inorganic compounds and as a result may increase the solubility of these compounds. See e.g. the review article of Saenger in Angewandte Chemie Int. Ed. 19, 344 (198~).
It is Applicant's own experience an~ supported by literature data that the solubility of a compound in water may increase very roughly by a factor 2-500 provided said compound is able to ~orm an inclusion-complex with one of the cyclodextrins.
The Steroid, however, would not benefit from such increase because its original solubility in water of ap-proximately 5x10-4 mg/ml would most ideally increase at most up to a level of about 0,1 mg/ml which is still in-sufficient for local administration o~ the Steroid in general and more in particular for ophthalmological ap-plication. Practical solubility tests carried out with ~,~ and r-cyclodextrin only confirmed this expectation.
Surprisingly, however, it was found that an inclusion complex formed between the Steroid and 2,6-dimethyl-~-cyclodextrin increased the solubility of the Stèroid in water from the original level of 5xlO 4 mg/ml up to a level o~ about 10 mg~ml, which means an increase of the solubility with the unexpectedly high factor of 10.000.
Thi6 increase of the Steroid's solubility in water renders a practical application of the Steroid possible in pharmaceutical preparations for local administration and especially in ophthalmological preparations.
The present invention therefore encompasses a phar-maceu~ical preparation for local administration, and especially an ophthalmological preparation comprising an aqueous solution of ll~-hydroxy-16~,17~,21-trimethyl-4_ pregnadiene 3,20-dione (the Steroid, Org 6216) and a partially alkylated ~-cyclodextrin.
A partially alkylated ~-cyclodextrin is a deriva-tive of ~-cyclodextrin (or cyclohepta~amylose) in which one or more hydroxy groups are alkylated. Examples of such partially alkylated ~-cyclodextrins are the 2-hydroxypropyl, 6-methyl, 2,3-dimethyl and in particu-lar the 2,6-dimethyl-~-cyclodextrin.
The solubility o~ the Steroid in water increases with increasing concentrations of partially alkylated ~-cyclodextrin until this solubility reaches its level-off phase or maximal level. This maximal level is ob-tained using relatively large amounts of partially alky-lated ~-cyalodextrins, roughly O.2-0.3 mmol. partially alkylated ~-cyclodextrin per mililiter water.
The maximal solubility o the 5tersid in water using 2,6-dimethyl~-cyclodextrin as the solubilizing agent amounts to about 9-10 mg/ml; at this level the 2,6-dimethyl-~-cyclodextrin concentration required is about 0,28 millimol per ml. A further increase of the cyclodextrin concentration contributes less effectively to a further improve~ent of the Steroid's sslubility.
The graph shows the increase o~ the solubility of the Steroid (Org 621~) with increasing 2,6-dimethyl-~-cyclodextrin concentrations.
' ~3~131 The solubility studies were per~ormed according to the method described ~elow which is well known in the litrature. Excess amounts of the Steroid were added to a~ueous solutions of 2,~-dimethyl-~cyclodextrin. These suspensions were shaken at room temperature during 5 days followad by an equilibration period of 3 days at room temperature. Then an aliquot was centrifuged and the supernatant was fil~ere~ t~hrough a 0,45 ~m membrane filter (Millipore: HV4, Millex). The samples were anal-ysed with the Perkin ~lmer Lambda 5 W/VIS spectropho-tometer. The absorbance was read and compared with a blanc and standard calibration curve. ~rom these data the concentration o~ Steroid dissolved in water was cal-culated. After calculation of the amount of Steroid dis-solved, a phase-solubility diagram was constructed by plotting the dissolved amounts of Steroid as a function of the concentratiGn of 2,6-dimethyl-~-cyclodextrin (see Graph).
From the curve obtained the complex stabllity con-stant K was calculated using the formula:
slope K =
SO (l-sloPe) SO = saturation concentration of Steroid without 2,6-dimethyl-~-cyclodxtrin.
slope = the slope of the initial part of the curve.
This complex-stability constant K i5 also a measure for the solubility of the Steroid in water. The higher this complex-stability constant, the better is the sta-bility of the complex and the higher is the solubility in water.
For comparati~e purposes the unexpected increase of solubility of the Steroid in water using 2,6 dimethyl-~-cyclodextrin, is compared with other more common cy-clodextrins. Th~ results are described in the following table:
.
~rad~ - ~ar~
1~0~
Cyclodextrin Steroid reference compounds Org 6216 _ - . 1 ~-cyclodextr~n K (ml.mmol. ) 380 Solubility (mg/ml) 4 x 10-2 R-cylodextriln X (ml.mmol.~ ) 3400 Solubility (mg/ml) 5 x 10 2 r-cvclodextr~ l K (ml.mmol. ) 9600 I
Solubility (mg/ml) 7 x 10 2 Part. alkylated cyclodextrin 2r6~dimethyl~
~aYsal~ I I
K (ml.mmol l) l 58000 Solubility (mg/ml) l 9 Solubility without cyclodextrin, mg/ml l 7 x 10-4 . ~ . - . , I
Besides the essential ingredients Steroid, par-tially methylated ~-cyclodextrin and water, the pharma-ceutical preparation according to the invention may con-tain other active substances and/or pharmaceutical aux-iliaries.
The preparation may optionally contain for example, preservatives, viscosity increasing agents, agents for rendering the solution isotonic, buf~ers for adapting the desired pH, surfac~ants etc., as well as the usual pharmaceutically acceptable carriers and/or diluents.
As already said the preparation according to the invention may be used for all kinds of local administra-tion, e.g. as injection preparation, intranasal prepara-tion, ear-drops, topical preparation (gel, ointment, foam, cream~, but is preferably used for ophthalmologi-cal purposes.
.
6 132~l3l A preparation for local administration is a prepa-ration that i~ locally active and does not exert a sig-nificant systemic effect.
The concentration of the Steroid in the pharmaceu-tical preparation according ~o the invention may vary somewhat depending upon the way of administration. The usual concentration, however, varies between 1 and 10 mg and more par~icularly between 5 and 10 mg per mililiter water. For ophthalmological purposes where usually only one or two drops are applied the concentration of the Steroid i~ preferably as high as possible, viz. about 9-10 mg per ml water.
~xamples 1. ToE~çal qel 2,6-dimethyl-~-cyclodextrin 50,0 g Org 6216 0,9 g pectine 5.0 g sugar 30,0 g water to 100 ml prepare complex, add pectin and ~issolve, add sugar adju~t pH to 3-4.
2. o/w emulslon (w = water phase, o = oil phase) 2,6-dimethyl-~-cylodextrin 185 g w org 6216 3,3 g w sodium laurylsulphate10 g w stearyl alcohol 250 g w white petrolatum250 g w methylhydroxybenzoate0,7 g w propylhydroxybenzoa~e3,7 g w water 370 g w propylene glycol120 g w 1192,7 g prepare oil ph~se and water phase separately at ele-vated temperature~ then, add oil pha~e to water phase and homogenize.
:;
' . ~ :
~, .
7 132n~ 31 3. Opthalmic solution (eye drop) Org 6216 4,5 g 2,6 dimethyl-~-cyclodextrin 250,0 g polyvinylalcohol 7,0 g Na2HPO4 3,8 g NaH2PO4 0, 8 g Chlorobutanol 2,5 g NaCl to isotonic Water for injections to 500 ml prepare complex, add other components, adjust to volume.
4. Injectable preparation Org 6216 9 mg 2,6-dimethyl-~-cyclodextrin 500 mg NaOH/HCl to pH 7 Mannitol to isotonic Water for injections to 1,0 ml prepare complex, add other components, adjust to volume.
5. otic ~renaration ~earL
2,6-dimethyl-~-cyclodextrin 125 Org 6216 2,25 g benzylalcohol 10 g sodium carhoxymethylcellulose 0,025 g propylene glycol 25,0 NaCl to isotonic NaOH/HCl to pH 7 Water for injections to 250 ml .
8 1~20131 6. To~ical foam Emulsion base Org 6216 7,1 g 2,6-dimethyl~-cyclodextrin 394,2 g miristic acid 12,6 g stearic acid 42,0 g cetylalcohol 3,9 g lanolin 1,6 g isopropylmyristate 12,6 g triethanolamine 26,3 g glycerin 37,1 g polyvinylpyrrolidone 2,7 g water 7QO,O ml Final 960 g smulsion bas 40 g hydrocarbon propellant A-46 7. Nasal ~reparation - Org 6216 90mg 2,6-dlmethyl-~-cyclodextrin 5000 mg benzalkoniumchloride 0,001 mg EDTA 0,01 mg NaOH/HC1 to pH 7 Mannitol to iæo-osmotic Water for injections to 10 ml ' .
' ' , ~ .
, : ' .
'' ' ' ; . .
2,6-dimethyl-~-cyclodextrin 125 Org 6216 2,25 g benzylalcohol 10 g sodium carhoxymethylcellulose 0,025 g propylene glycol 25,0 NaCl to isotonic NaOH/HCl to pH 7 Water for injections to 250 ml .
8 1~20131 6. To~ical foam Emulsion base Org 6216 7,1 g 2,6-dimethyl~-cyclodextrin 394,2 g miristic acid 12,6 g stearic acid 42,0 g cetylalcohol 3,9 g lanolin 1,6 g isopropylmyristate 12,6 g triethanolamine 26,3 g glycerin 37,1 g polyvinylpyrrolidone 2,7 g water 7QO,O ml Final 960 g smulsion bas 40 g hydrocarbon propellant A-46 7. Nasal ~reparation - Org 6216 90mg 2,6-dlmethyl-~-cyclodextrin 5000 mg benzalkoniumchloride 0,001 mg EDTA 0,01 mg NaOH/HC1 to pH 7 Mannitol to iæo-osmotic Water for injections to 10 ml ' .
' ' , ~ .
, : ' .
'' ' ' ; . .
Claims (4)
1. A pharmaceutical preparation for local administra-tion comprising an aqueous solution of 11-.beta.-hydroxy-16.alpha.,17.alpha.,21-trimethyl.DELTA.1,4-pregnadiene 3,20-dione and a partially alkylated .beta.-cyclodextrin.
2. Preparation according to claim 1 comprising 2,6-dimethyl-.beta.-cyclodextrin as the partially alkylated .beta.-cyclodextrin.
3. Preparation according to claim 1 or 2 especially in-tended for ophthalmological purposes.
4. Preparation according to claim 3 comprising 5-10 mg of the Steroid per ml water.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14388888A | 1988-01-14 | 1988-01-14 | |
US07/143,888 | 1988-01-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1320131C true CA1320131C (en) | 1993-07-13 |
Family
ID=22506113
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000588137A Expired - Fee Related CA1320131C (en) | 1988-01-14 | 1989-01-13 | Aqueous pharmaceutical preparation containing 11.beta.-hydroxy steroids |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0326196B1 (en) |
JP (1) | JPH02706A (en) |
AT (1) | ATE74003T1 (en) |
CA (1) | CA1320131C (en) |
DE (1) | DE68901043D1 (en) |
ES (1) | ES2037385T3 (en) |
GR (1) | GR3005035T3 (en) |
Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE100712T1 (en) * | 1989-05-24 | 1994-02-15 | Innovet Inc | HYPOALLERGENIC ANESTHETIC/HYPNOTIC STEROID MEDICATION. |
HU210921B (en) * | 1990-03-28 | 1995-09-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing inclusion complexes of n-ethoxycarbonyl-3-morpholino-sydnonimine formed with cyclodextrines and pharmaceutical compositions containing them |
US5494901A (en) * | 1993-01-05 | 1996-02-27 | Javitt; Jonathan C. | Topical compositions for the eye comprising a β-cyclodextrin derivative and a therapeutic agent |
US5977180A (en) * | 1994-07-11 | 1999-11-02 | Pate; David W. | Anandamide analog compositions and method of treating intraocular hypertension using same |
US5631297A (en) * | 1994-07-11 | 1997-05-20 | Pate; David W. | Anandamides useful for the treatment of intraocular hypertension, ophthalmic compositions containing the same and methods of use of the same |
JP2920611B2 (en) * | 1995-12-11 | 1999-07-19 | 株式会社シーエーシー | Topical treatment for dermatitis |
US8512718B2 (en) | 2000-07-03 | 2013-08-20 | Foamix Ltd. | Pharmaceutical composition for topical application |
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Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU181703B (en) * | 1980-05-09 | 1983-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing aqueus solutuins of water insoluble or hardly soluble vitamines, steroides, localanesthetics, prostanoides and non-steroid and antiphlogistic agents |
US4383992A (en) * | 1982-02-08 | 1983-05-17 | Lipari John M | Water-soluble steroid compounds |
DE3346123A1 (en) * | 1983-12-21 | 1985-06-27 | Janssen Pharmaceutica, N.V., Beerse | PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF |
US4686214A (en) * | 1985-10-30 | 1987-08-11 | Alcon Laboratories, Inc. | Anti-inflammatory compounds for ophthalmic use |
-
1989
- 1989-01-09 DE DE8989200039T patent/DE68901043D1/en not_active Expired - Fee Related
- 1989-01-09 ES ES198989200039T patent/ES2037385T3/en not_active Expired - Lifetime
- 1989-01-09 EP EP89200039A patent/EP0326196B1/en not_active Expired - Lifetime
- 1989-01-09 AT AT89200039T patent/ATE74003T1/en not_active IP Right Cessation
- 1989-01-12 JP JP1005850A patent/JPH02706A/en active Pending
- 1989-01-13 CA CA000588137A patent/CA1320131C/en not_active Expired - Fee Related
-
1992
- 1992-06-25 GR GR920401364T patent/GR3005035T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
GR3005035T3 (en) | 1993-05-24 |
DE68901043D1 (en) | 1992-04-30 |
ATE74003T1 (en) | 1992-04-15 |
ES2037385T3 (en) | 1993-06-16 |
JPH02706A (en) | 1990-01-05 |
EP0326196A3 (en) | 1989-10-04 |
EP0326196A2 (en) | 1989-08-02 |
EP0326196B1 (en) | 1992-03-25 |
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